Every year, millions of people seek medical treatments for acute or overuse injuries of soft tissue, for example, injury to ligaments (sprain), or musculo-tendinous structures (strain).
In the example of sprain, soft tissue sprain injury can vary from first degree (slight ligamentous tear) to second degree (greater tearing with blood clot formation and moderate functional impairment) to third degree (total separation of the ligament associated with loss of function and mechanical stability). Symptoms include pain, heat, redness, swelling and functional loss. Therapies for sprain are directed at decreasing inflammation and pain. Treatment of mild to moderate sprains (first and second degrees) is usually done at home with rest, ice, compression and elevation (the so-called RICE treatment, rest-ice-compression-elevation), the use of nonsteroidal anti-inflammatory drugs (NSAIDs) that include aspirin, ibuprofen and naproxen, or immobilization with various devices including braces or plaster casts. More severe injury may require splinting, casting, or even surgical stabilization.
Soft tissue injury can also include strains that result from a traumatic injury or from improper or overuse of a muscle-tendon unit characterized by pain, swelling and impaired movement when using the injured muscles. Treatment includes cold or heat compresses, immobilization, and/or the use of NSAIDs.
Soft tissue injuries, such as sprains and strains, can affect any ligamentous or muscle-tendon structure and include, but are not limited to the ligaments and tendons associated with the following joints and structures: foot, plantar fascia, ankle, knee, patellar-femoral structure, hip, ilio-tibial band, back, shoulder, elbow, wrist, hand, jaw, and neck.
Hyaluronic acid (hereinafter, “HA”), also known as hyaluronan, hyaluronate or sodium hyaluronate, is an abundant non-sulfated glycosaminoglycan that is present in all joint tissues. HA is a naturally occurring linear polysaccharide composed of β-1,4-linked D-glucuronic acid-(β-1,3)-N-acetyl-D-glucosamine dissacharide units. In its native form, HA exists as a high molecular weight polymer (about 106-107 Da). In normal human synovial fluid, the molecular weight of HA is between about 6-7×106 Da, and the concentration is about 2-4 mg/ml. HA synthesized by synoviocytes is responsible for the viscoelastic properties of synovial fluid and plays a fundamental role in the maintenance of the trophic status of the cartilage. In joint disease there is a reduction in both the concentration and molecular weight of HA.
Intra-articular injection of exogenous high molecular weight HA (>5×106 Da) was found to improve function in humans with osteoarthritis or rheumatoid arthritis (Maheu et al., Int. J. Clin. Pract. 56:804-813, 2002; Matsuno et al., Inflamm. Res. 48:154-159, 1999). Three to five weekly intra-articular injections were required to significantly improve the pain and the functional status of patients with osteoarthritis, the effect lasting at least six months and up to one year after treatment cessation (Maheu et al., Int. J. Clin. Pract. 56:804-813, 2002). It was believed that intra-articular administration of HA may reverse HA degradation observed in osteoarthritis and to restore synovial fluid viscosity (viscosupplementation) (Balazs and Denlinger, J. Rheumatol. 20:3-9, 1993). Intra-articular administration of HA was also found to improve function in humans with acute knee injury (Zattono et al., Eur. J. Rheumatol. Inflamm. 15:53-69, 1995). While intra-articular administration of HA is has been proposed for various conditions, it is a complex process as locating the joint cavity during an intra-articular procedure is relatively difficult. Improper injection may lead to a variety of complications.
Peri-articular administration to treat joint injury has been described in European Patent No. 1677806 issued Nov. 19, 2008. The efficacy of periarticular administration of HA to patients with ankle sprain was shown to compare favourably with the efficacy obtained with celecoxib, an inhibitor of cyclooxygenase-2, or naproxen, an NSAID.
Another study (Petrella R J, Petrella M J, Cogliano A. Periarticular hyaluronic acid in acute ankle sprain. Clinical Journal of Sports Medicine 2007; 17(4):251-257) describes significant improvements in pain and function with HA injections in lateral ankle sprains in 158 athletes randomized to active treatment versus placebo. Not only was the effect greater than placebo, but this was associated with a high degree of satisfaction among patients in both in the short- and longer-term (3 months) as well as reduced pain and more rapid return to sport. However, the effect of peri-articular HA has a time of onset of about 4 days.
There is a lack of clear evidence to support use of Botulinum toxin in treatment of soft tissue injury. Botulinum toxin has been used in the treatment of many conditions, including detrusor instability, myofascial pain syndromes, dystonia, and writer's cramp. The direct impact of Botulinum toxin on pain pathways in many of these conditions suggest it may be helpful immediately on soft tissue pain. However, the results of it's reported use for treatment of lateral epicondylitis have not been encouraging. In one study (Hayton M J, Santini A J, Hughes P J, Frostick S P, Trail I A, Stanley J K. Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled, pilot study. J Bone Joint Surg Am 2005; 87:503-507.), there was no observed difference between botulinum toxin injection and normal saline placebo in pain and grip strength. A side effect of botulinum toxin can be reduced function of soft tissue at the site of administration. A previous report (Wong S M, Hui A C F, Tong P Y, Poon D W F, Yu E, Wong L K S. Treatment of lateral epicondylitis with botulinum toxin. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2005; 143:793-797) describes unwanted side effects of minor paresis and weakness. Other sources of weakness may be secondary to neurotransmitter release dysfunction at the synaptic terminal. HA, on the contrary, injected locally at the site of injury has not appeared to have any precipitation of systemic risk of adverse events as well as any reported local adverse effects.
There are many reports of NSAID use for treating joint injury. NSAIDs effectively reduce pain and swelling and disability associated with joint injury, but this may not alter the clinical course of the ankle sprain regarding return to sport and may also cause significant adverse events, including gastrointestinal intolerance and serious events such as ulcers and bleeding.
Most known medical therapies for sprain and strain, whether directed to decreasing inflammation and/or pain, have proven to be less than adequate. There is a continuing need for novel compositions and methods for treating soft tissue and in particular, soft tissue injury such as sprain and strain.